The dynorphin/kappa opioid receptor mediates adverse immunological and behavioral outcomes induced by repetitive blast trauma.
The dynorphin/kappa opioid receptor mediates adverse immunological and behavioral outcomes induced by repetitive blast trauma.
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DOI：
10.1186/s12974-022-02643-3
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发表时间：
2022-12-03
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
与轻度创伤性脑损伤 (mTBI)、创伤后应激障碍 (PTSD) 和慢性疼痛相关的不良病理生理和行为结果在爆炸暴露后很常见，并导致生活质量下降，但潜在的机制和预防/治疗选择仍然有限。强啡肽/κ阿片受体（KOR）系统有助于调节对压力和损伤的行为和炎症反应；然而，对于暴露于爆炸的人类或动物来说，它的潜在机制尚未得到研究。我们假设爆炸诱导的 KOR 激活会介导与炎症和情感行为反应相关的不良后果。 C57Bl/6 成年雄性小鼠单独或重复暴露于假手术（仅麻醉）或由气动冲击管传递的冲击波。在重复爆炸或假暴露之前 72 小时施用选择性 KOR 拮抗剂去甲 BNI 或载体（盐水）。暴露后 10 分钟或 4 小时收集血清和大脑，分别进行强啡肽 A 样免疫反应性和细胞因子测量。暴露后 1 个月，小鼠接受了一系列与爆炸创伤人类报告的不良后果相关的行为测定。重复而非单次爆炸暴露会导致脑部强啡肽 A 样免疫反应性增加。 NorBNI 预处理可阻断或显着减少暴露后 4 小时由爆炸引起的血清和脑细胞因子（包括 IL-6）增加，以及暴露后 1 个月的厌恶/焦虑样行为功能障碍。我们的研究结果表明，强啡肽/KOR 系统在重复爆炸暴露后作为生化和行为功能障碍的调节剂发挥着先前未报道的作用，并强调该系统作为潜在的预防/治疗目标。
Adverse pathophysiological and behavioral outcomes related to mild traumatic brain injury (mTBI), posttraumatic stress disorder (PTSD), and chronic pain are common following blast exposure and contribute to decreased quality of life, but underlying mechanisms and prophylactic/treatment options remain limited. The dynorphin/kappa opioid receptor (KOR) system helps regulate behavioral and inflammatory responses to stress and injury; however, it has yet to be investigated as a potential mechanism in either humans or animals exposed to blast. We hypothesized that blast-induced KOR activation mediates adverse outcomes related to inflammation and affective behavioral response. C57Bl/6 adult male mice were singly or repeatedly exposed to either sham (anesthesia only) or blast delivered by a pneumatic shock tube. The selective KOR antagonist norBNI or vehicle (saline) was administered 72 h prior to repetitive blast or sham exposure. Serum and brain were collected 10 min or 4 h post-exposure for dynorphin A-like immunoreactivity and cytokine measurements, respectively. At 1-month post-exposure, mice were tested in a series of behavioral assays related to adverse outcomes reported by humans with blast trauma. Repetitive but not single blast exposure resulted in increased brain dynorphin A-like immunoreactivity. norBNI pretreatment blocked or significantly reduced blast-induced increase in serum and brain cytokines, including IL-6, at 4 h post exposure and aversive/anxiety-like behavioral dysfunction at 1-month post-exposure. Our findings demonstrate a previously unreported role for the dynorphin/KOR system as a mediator of biochemical and behavioral dysfunction following repetitive blast exposure and highlight this system as a potential prophylactic/therapeutic treatment target.
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